SMJ 2003 48(3): 64-68
McDougall C, Perry CG, Sattar N, Petrie JR
Division of Cardiovascular and Medical Sciences, Glasgow Royal Infirmary
Author for correspondence: Dr JR Petrie jrpls@clinmed.gla.ac.uk
ABSTRACT
The benefits of statins in reducing cardiovascular risk are well documented and their use in secondary prevention of cardiovascular disease is widely advocated. Moreover, numerous studies have demonstrated the benefit of statins in primary prevention. Current guidelines suggest arbitrary cut-off points, based on cost-effectiveness, for the level of cardiovascular risk at which people should receive statin therapy in this context. However, the results of recent studies, discussed herein, and the probability of falling costs, will result in recommendations to treat larger groups of people with these safe and effective drugs.
Abbreviations: CHD, coronary heart disease; HDL, high-density lipoprotein; HMG-CoA, 3-hydroxymethyl 3-glutaryl coenzyme A; LDL, low-density lipoprotein; MI, myocardial infarction; TC, total cholesterol; RCT, randomised-controlled trial;
INTRODUCTION
Over recent years, statins [3-hydroxymethyl 3-glutaryl coenzyme A (HMG-CoA) reductase inhibitors] have been shown to be effective in reducing serum cholesterol and in decreasing cardiovascular risk (1-6) . They now play a major role in the treatment of patients with cardiovascular disease and diabetes and are increasingly used in primary prevention of cardiovascular events in healthy individuals. However, many health care professionals in both primary and secondary care remain uncertain when and whether to prescribe a statin. The literature is extensive and rapidly developing - when taken into consideration with cost effectiveness analyses it can be confusing.
Statins are thought to act primarily by reducing serum low-density lipoprotein (LDL) cholesterol. They also have moderate effects on increasing high-density lipoprotein (HDL) concentration and reducing serum triglycerides. They competitively inhibit HMG-CoA reductase (the rate-limiting enzyme in cholesterol synthesis), increase the expression of LDL receptors and increase receptor-mediated clearance from plasma. In addition to effects on lipids, statins are now thought to confer a number of pleiotropic actions, including anti-inflammatory effects, which are likely to contribute to their beneficial effects (7). They are generally well tolerated. The major adverse effect is myositis which is rare and appears chiefly to affect patients with complex medical problems or multiple drug therapies. Cerivastatin was voluntarily withdrawn by its manufacturer in 2001 because of 31 reports of fatal rhabdomyolysis, 12 of which were associated with concomitant use of gemfibrozil (8). It has been recommended that any patient receiving statin therapy who experiences muscle fatigue or pain, should have a serum creatine kinase level measured.
SECONDARY PREVENTION
There have been three major randomised, double-blind placebo-controlled trials assessing the effect of statins on cardiovascular risk in patients with pre-existing cardiovascular disease: the Scandinavian Simvastatin Survival Study (4S 1994), the Cholesterol and Recurrent Events Study which was conducted in the US and Canada (CARE 1996), and the Long-term Intervention with Pravastatin in Ischaemic Disease Study carried out in Australia and New Zealand (LIPID 1998). Active treatment with simvastatin was associated with a significant reduction in all cause mortality, coronary heart disease (CHD) related death and non-fatal MI in 4S, while in CARE pravastatin produced a reduction in CHD related deaths, non-fatal MI, strokes and coronary revascularisation (with no reduction in all cause mortality). Patients with a wide range of total serum cholesterol (4.08.0 mmol/l) in LIPID who were randomised to the active treatment group, benefited from a significant reduction in MI, unstable angina, CHD related deaths and all cause mortality.
The use of statins in secondary prevention is therefore undisputed. Patients with established coronary heart disease are at high risk of further cardiovascular events (9). In 4S the average annual risk of a cardiovascular event was approximately 4.5%, and the number needed to treat (NNT) over five years with simvastatin in order to prevent one major coronary event was only 13. A subsequent cost-effectiveness analysis of these data by the 4S investigators determined that the cost of simvastatin therapy per life-year gained after a first MI was £5502 (10). It should be noted that this calculation is based on benefits over five years of treatment as opposed to lifelong, thus potentially under-estimating the cost-effectiveness of therapy.
PRIMARY PREVENTION
Well-designed studies, involving large numbers of patients, have also shown the benefits of statins in primary prevention of cardiovascular disease. The West of Scotland Coronary Prevention Study (WOSCOPS, 1995 1 ) and the Air Force / Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS 1998 4 ) were large randomised double-blind placebo-controlled primary prevention studies, assessing the effects of pravastatin and lovastatin respectively. The AFCAPS/TexCAPS study cohort consisted of 6605 healthy individuals with a mean total serum cholesterol of 5.71mmol/l and mean LDL cholesterol of 3.89mmol/l. WOSCOPS however, specifically targeted 6595 males with no history of vascular disease but an elevated total cholesterol (5.0 8.0mmol/l). AFCAPS/TexCAPS demonstrated a lovastatin associated reduction in first MI, unstable angina and coronary revascularisation procedures. Active treatment in WOSCOPS was associated with a reduction in cardiovascular death and in non-fatal MI, and a trend towards reduction in all cause mortality.
The benefits of statins have therefore been well documented in different groups of people including those with no previous history of cardiovascular disease and normal cholesterol levels. Does this mean that we should prescribe statin therapy in all people who meet the entry criteria for the aforementioned primary and secondary prevention studies? For example, if the WOSCOPS criteria were applied to the general population of Scotland, approximately 11% of apparently healthy 35-64 year-olds would merit treatment (11). Moreover, approximately 3.8 million people in England alone have an annual CHD risk of 1.5%, which is the level of risk of the WOSCOPS cohort (12). At current prices, the cost could potentially be overwhelming and unsustainable. Strategies have therefore been devised to direct treatment towards those who will experience the greatest reduction in cardiovascular events in order to maximise the benefits accruing from a pressurised prescribing budget i.e. to implement an explicit form of rationing.
Use of statins in primary prevention of cardiovascular disease in patients who may or may not have other cardiovascular risk factors is therefore much more complicated. Policy in this area must take account of four major factors: 1) number needed to treat data; 2) proportion of the population to be treated; 3) cost-effectiveness of the treatment; 4) total cost. Patients in AFCAPS/TexCAPS had a baseline annual risk of cardiovascular events of 0.5%. The absolute reduction in cardiovascular endpoints in the primary prevention studies, although statistically significant, was lower than that seen in these secondary prevention studies. Thus, the number of patients requiring to be treated to prevent one event in WOSCOPS was 40 compared to 13 in 4S.
Formal health economic analyses of cost-effectiveness have also been performed in primary prevention (13-15) . Those based on serum cholesterol levels alone have estimated the cost per life year gained to range from £14 000 to £297,000. Serum cholesterol is a poor predictor of cardiovascular risk when no other risk factors are taken into consideration (16).
A more recent analysis, however, has evaluated cost per life-year gained at differing levels of CHD risk (12). It estimated costs per life year gained for annual CHD risk levels of 3.0%, 2.0% and 1.5% at £8200, £10 700 and £12 500 respectively. This analysis reported that in the cases of secondary prevention and primary prevention with an annual CHD risk of 3.0%, the numbers needed to treat are acceptable at 13 and 20 respectively. These values are comparable with other widely used treatments (17) and this would entail treating approximately 8% of the UK population. The authors, however, expressed grave concerns regarding widespread treatment of those with a lower level of annual CHD risk. For example, in the case of those with an annual CHD risk of 1.5%, this would involve treating approximately 25% of the population, consuming 90% of the current total UK drug budget (18).
In addition, a cost-effectiveness analysis based on WOSCOPS data has assessed the economic implications for prescribing in Scotland were its recommendations to be fully implemented (11). If all of those fitting the entry criteria were treated, ie those with an approximate annual cardiovascular risk of 1.5%, the cost per life-year gained would be £20,375. If patients with an annual risk of >2.0% were to be treated, as per the guideline of the joint commission of The European Society of Cardiology, European Atherosclerosis Society, and European Society for Hypertension in 1998 (19), the cost per life year gained would be £13 995. In the case of treating only those with an annual risk of 3.0%, the cost per life year gained would be £9680 (11).
Such cost-effectiveness analyses are critically affected by drug price. This year will see the end of Merck Sharp & Dohmes patent for simvastatin and the probability of less expensive generic formulations. This, in turn, is very likely to lower the threshold of risk at which statin prescribing becomes cost-effective.
CURRENT PRACTICE AND GUIDELINES
In contrast to the above-mentioned European Guidelines, current trends in Scotland are to treat those with an annual CHD risk of 3%. This is based upon the Standing Medical Advisory Committee report in 1997 which advised that patients with a coronary heart disease risk of >3% per year should be treated with statins (20).
Two main methods of evaluating risk are available: the Joint British Societies coronary risk prediction chart and the new Sheffield Table. One comparison of these two methods suggested that they are equally sensitive and specific in estimating risk of coronary heart disease, and encouraged practitioners to use the tool with which they were most comfortable (21).
There are major concerns however, that these tables are not accurate in assessing the degree of risk of CHD in people with type 2 diabetes, as they are based on data from the Framingham cohort in which the subgroup with diabetes was very small (22). In any case, evidence suggests that statins are often solely prescribed on the basis of serum cholesterol alone, rather than in the context of CHD risk (23). A further audit of prescribing practices in patients with coronary heart disease (i.e. secondary prevention), revealed that of 24 431 patients with documented coronary artery disease, 42% of patients had not had their cholesterol recorded and only 16% of these patients were receiving statin therapy (24).
The third report of The Expert Panel on Detection and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, ATP III) (25) was published in the US in 2001. It is an extensive document outlining the specific rationale underlying the treatment of hypercholesterolaemia. It is based on consensus and expert opinion rather than formal assessment and grading of evidence. These guidelines categorise the population into three major risk groups:
1) CHD risk equivalents diabetes, other forms of occlusive arterial disease and those with multiple risk factors (cigarette smoking, hypertension, low HDL cholesterol, family history of premature CHD, age). These patients have a 20% risk of a major coronary event over the next 10 years and a serum LDL-cholesterol target of <2.5mmol/l.
2) people with multiple risk factors, a 10 year risk for CHD of 10-20%, and an LDL cholesterol target of <3.2 mmol/l
3) people with one risk factor, a 10-year risk of <10%, and an LDL cholesterol target of <4.0 mmol/l.
Thus, the report advocates the use of lipid-lowering therapy in patients with a 10-year CHD risk of >10%, with the target level of LDL cholesterol depending upon the overall CHD risk. For patients with a 10-year risk of <10%, changes in lifestyle (reduced intake of saturated fats and cholesterol, weight loss and increasing levels of physical exercise) are advocated to reduce LDL. However, in the event of exceptionally high serum cholesterol or a single severe risk factor, treatment with statins is left at the discretion of the physician.
The recommendations on the use of lipid lowering therapies in the primary prevention of CHD, were also made on the basis of a systematic review of the evidence available in 1999 by the Scottish Intercollegiate Guideline Network (SIGN 40) (26). This document recommended initial modification of lifestyle factors, with statin therapy if total serum cholesterol was >5.0mmol/l and the 10-year risk of a major coronary event was >30%, based on the Joint British Societies Coronary Risk Prediction Chart.
IS
DIABETES A CHD RISK EQUIVALENT?
An emerging body of opinion, including ATP III, suggests that secondary prevention evidence should be extrapolated to patients with type 2 diabetes and hypercholesterolaemia. Haffner has reported that the seven-year rate of MI in patients with type 2 diabetes (20.2%) was greater than in non-diabetic individuals with established CHD (18.8%) (9). However, a study more relevant to the Scottish population (performed in Tayside), has reported a higher incidence of death from all causes, CHD related mortality and MI in patients with established CHD than in those patients with type 2 diabetes (27). No studies published to date have assessed the effect of statins on the development of cardiovascular disease specifically in people with type 2 diabetes. The results of the Collaborative Atorvastatin Diabetes Study (CARDS), a multicentre RCT investigating the effects of statins in primary prevention of cardiovascular disease in diabetic patients, are awaited with interest (28).
a)
The Heart Protection Study
None of the guidelines have so far been revised in order to take account of the findings of this large multi-centre study, coordinated from Oxford, involving 20 536 male and female patients and published in July 2002 (5). This RCT assessed the effects of simvastatin vs placebo in patients with CHD and average or below average serum cholesterol, non-coronary vascular disease, or diabetes over a five-year period. Women and elderly patients were well represented. The rationale was to assess the effects of statin therapy in people at high risk of a cardiovascular event, but in whom existing evidence for treatment was limited. Primary outcomes were all-cause mortality and fatal and non-fatal vascular events. The results revealed a significant reduction in all-cause mortality, coronary death rate and non-fatal MI along with a significant reduction in fatal and non-fatal strokes and coronary revascularisation associated with active treatment. These reductions were significant by the second year of follow-up. Reductions in event rates were similar in each subgroup studied, including the subgroup in whom initial total cholesterol was <5.0 mmol/l (LDL cholesterol <3.0 mmol/l), and in the subgroup with type 2 diabetes. Guidelines will clearly require updating in light of these findings. Absolute risk reduction was only marginally attenuated in subjects at lower baseline risk of CHD, with no clear threshold. One of the other major points emerging from this study is that decisions regarding statin treatment may be better based on overall cardiovascular risk rather than CHD risk alone.
b)
The Prospective Study of Pravastatin in the Elderly at Risk Study (PROSPER)
The results of the Pravastatin in elderly individuals at risk of vascular disease (PROSPER) study were published in November 2002 (29). It assessed the effect of pravastatin 40 mg daily in 5804 patients aged between 70 and 82 years who either had pre-existing vascular disease or were at high risk. Participants were from Scotland, Ireland and the Netherlands, with total serum cholesterol ranging from 4.0-9.0 mmol/l. Follow-up was for a mean of 3.2 years with primary endpoints death from CHD, non-fatal MI and fatal or non-fatal stroke. Other endpoints assessed were disability, transient ischaemic attacks and cognitive function. Results revealed a significant 15% relative risk reduction in CHD related death and non-fatal MI associated with active treatment, which was smaller than anticipated despite identity of observed and predicted CHD event rates (16%) in the placebo group. No significant reduction in stroke was detected although there was a trend towards a reduction in transient ischaemic attacks in those treated with pravastatin, but no reduction in disability or in cognitive decline.
Possible explanations for the results have already been suggested. The relatively short period of follow-up may have diluted the overall risk reduction. Moreover, the rate of stroke in the study population was lower than expected, diminishing statistical power; longer follow-up may be required to detect a reduction in stroke, although this has been disputed (30). Interestingly, subgroup analysis suggested that the observed reductions in CHD risk to occurred mainly in men rather than women, although this was not hypothesised a priori.
c)
The Antihypertensive and Lipid-Lowering Treatment to prevent heart Attack Trial
(ALLHAT)
The results of this large RCT, which took place in a number of primary care centres throughout North America, were published in December 2002 (31). 10,355 participants (against a target of 20,000) were recruited into the lipid-lowering arm (ALLHAT-LLT) from the main study, a four-armed antihypertensive trial comparing the antihypertensive effects of amlodipine, lisinopril, and doxazosin with chlorthalidone. Participants were aged 55 years or older, with hypertension, and fasting LDL cholesterol levels of 3.1 to 4.9 mmol/l. Mean age was 66 years, 49% were women and 35% had type 2 diabetes; they were randomised in a non-blinded fashion to receive either pravastatin 40 mg/day or usual care. The main aims of ALLHAT-LLT were to evaluate the effects of cholesterol reduction on all-cause mortality in a hypertensive cohort, and to assess CHD reduction in populations previously excluded or under-represented in major trials such as women, older people or those with type 2 diabetes. Unusually, because of the planned size of the trial, the primary outcome measure of the lipid arm was all-cause mortality, with secondary outcomes including nonfatal MI, cause-specific mortality and cancer. Results demonstrated no significant difference in all-cause mortality between the two groups, and the observed reduction in rates of CHD and stroke in the pravastatin treated group did not reach statistical significance. These surprisingly negative findings have been attributed to a modest reduction in total cholesterol (9.6%) and LDL cholesterol (16.7%) in those allocated to pravastatin compared to usual care. Indeed, 30% of those on active treatment had stopped it by year six and a similar percentage of the usual care group were receiving non-study lipid-lowering therapy by this time (in comparison with 6.5% of the pravastatin group).
CONCLUSIONS
The benefits of statins in reducing cardiovascular risk are well documented. People with an annual cardiovascular risk as low as 0.5% per year can benefit. To date, the only study cohort wherein no benefit was demonstrated was in ALLHAT-LLT, perhaps for the reasons outlined above. If resources were unlimited, it would remain an immense undertaking to identify all in the general population who would benefit. There is evidence that existing (conservative) guidelines are not being followed, and even patients at high risk of CHD are not being targeted (23); a more realistic goal for the short-term would be to ensure that all patients with pre-existing CHD and those at high risk were appropriately treated in order to make an impact on the burden of CHD.
In light of the results of HPS it appears that statins confer similar reductions in absolute risk of cardiovascular disease in groups at various levels of CHD risk, thus making it increasingly difficult to draw an arbitrary line to decide who merits treatment. There is conflicting evidence on whether type 2 diabetes should be regarded as a CHD risk equivalent with secondary prevention guidelines consequently being applied to these patients. The results of the diabetes subgroup of HPS suggest that patients with type 2 diabetes and no previous history of CHD, treated with simvastatin, do derive benefit in terms of a reduction in all vascular events - to a similar degree to those with a previous history of cerebrovascular or peripheral vascular disease.
Current evidence suggests that most middle-aged and many elderly people could benefit from statin therapy and it may become increasingly difficult from an ethical viewpoint to restrict treatment to certain groups. In the longer-term, as the price of therapy falls, it will become more cost-effective to treat lower risk groups. This will be an iterative process as evidence from RCTs is routinely incorporated into continually updated clinical guidelines, and implementation audited in increasingly sophisticated clinical networks. The age of statins has also been the era when evidence-based medicine has come of age.
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